The present invention relates to novel tricyclic heteroaromatic compounds and their derivatives useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are inhibitors of matrix metalloproteinases, e.g., gelatinase A (MMP-2), collagenase-3 (MMP-13), and stromelysin-1 (MMP-3). More particularly, the novel compounds of the present invention are useful in the treatment of atherosclerotic plaque rupture, aortic aneurism, heart failure, left ventricular dilation, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound repair, cancer, inflammation, pain, arthritis, osteoporosis, multiple sclerosis, renal disease, and other autoimmune or inflammatory disorders dependent on the tissue invasion of leukocytes or other activated migrating cells. Additionally, the compounds of the present invention are useful in the treatment of acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer""s disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson""s disease, Huntington""s disease, prion diseases, myasthenia gravis, and Duchenne""s muscular dystrophy.
Gelatinase A and stromelysin-1 are members of the matrix metalloproteinase (MP) family (Woessner J. F., FASEB J., 1991;5:2145-2154). Other members include fibroblast collagenase, neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2, stromelysin-3, matrilysin, collagenase 3 (Freije J. M., Diez-Itza I., Balbin M., Sanchez L. M., Blasco R., Tolivia J., and Lopez-Otin C., J. Biol. Chem., 1994;269:16766-16773), and the newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65).
The catalytic zinc in matrix metalloproteinases is a focal point for inhibitor design. The modification of substrates by introducing chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation.
The ability of the matrix metalloproteinases to degrade various components of connective tissue makes them potential targets for controlling pathological processes. For example, the rupture of an atherosclerotic plaque is the most common event initiating coronary thrombosis. Destabilization and degradation of the extracellular matrix surrounding these plaques by MMPs has been proposed as a cause of plaque fissuring. The shoulders and regions of foam cell accumulation in human atherosclerotic plaques show locally increased expression of gelatinase B, stromelysin-l, and interstitial collagenase. In situ zymography of this tissue revealed increased gelatinolytic and caseinolytic activity (Galis Z. S., Sukhova G. K., Lark M. W., and Libby P., xe2x80x9cIncreased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques,xe2x80x9d J. Clin. Invest., 1994;94:2494-2503). In addition, high levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., Murphy G., and Humphries S., xe2x80x9cLocalization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization,xe2x80x9d Proc. Nat""l. Acad. Sci., 1991;88:8154-8158).
Inhibitors of matrix metalloproteinases will have utility in treating degenerative aortic disease associated with thinning of the medial aortic wall. Increased levels of the proteolytic activities of MMPs have been identified in patients with aortic aneurisms and aortic stenosis (Vine N. and Powell J. T., xe2x80x9cMetalloproteinases in degenerative aortic diseases,xe2x80x9d Clin. Sci., 1991;81:233-239).
Heart failure arises from a number of diverse etiologies, but a common characteristic is cardiac dilation, which has been identified as an independent risk factor for mortality (Lee T. H., Hamilton M. A., Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H., and Walden J. A., xe2x80x9cImpact of left ventricular size on the survival in advanced heart failure,xe2x80x9d Am. J. Cardiol., 1993;72:672-676). This remodeling of the failing heart appears to involve the breakdown of extracellular matrix. Matrix metalloproteinases are increased in patients with both idiopathic and ischemic heart failure (Reddy H. K., Tyagi S. C., Tjaha I. E., Voelker D. J., Campbell S. E., and Weber K. T., xe2x80x9cActivated myocardial collagenase in idiopathic dilated cardiomyopathy,xe2x80x9d Clin. Res., 1993;41:660A; Tyagi S. C., Reddy H. K., Voelker D., Tjara I. E., and Weber K. T., xe2x80x9cMyocardial collagenase in failing human heart,xe2x80x9d Clin. Res., 1993;41:681A). Animal models of heart failure have shown that the induction of gelatinase is important in cardiac dilation (Armstrong P. W., Moe G. W., Howard R. J., Grima E. A., and Cruz T. F., xe2x80x9cStructural remodeling in heart failure: gelatinase induction,xe2x80x9d Can. J. Cardiol., 1994; 10:214-220), and cardiac dilation precedes profound deficits in cardiac function (Sabbah H. N., Kono T., Stein P. D., Mancini G. B., and Goldstein S., xe2x80x9cLeft ventricular shape changes during the course of evolving heart failure,xe2x80x9d Am. J. Physiol., 1992;263:H266-270).
Neointimal proliferation, leading to restenosis, frequently develops after coronary angioplasty. The migration of vascular smooth muscle cells (VSMCs) from the tunica media to the neointima is a key event in the development and progression of many vascular diseases and a highly predictable consequence of mechanical injury to the blood vessel (Bendeck M. P., Zempo N., Clowes A. W., Galardy R. E., and Reidy M., xe2x80x9cSmooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat,xe2x80x9dCirculation Research, 1994;75:539-545). Northern blotting and zymographic analyses indicated that gelatinase A was the principal MMP expressed and excreted by these cells. Further, antisera capable of selectively neutralizing gelatinase A activity also inhibited VSMC migration across basement membrane barrier. After injury to the vessel, gelatinase A activity increased more than 20-fold as VSMCs underwent the transition from a quiescent state to a proliferating, motile phenotype (Pauly R. R., Passaniti A., Bilato C., Monticone R, Cheng L., Papadopoulos N., Gluzband Y. A., Smith L., Weinstein C., Lakatta E., and Crow M. T., xe2x80x9cMigration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation,xe2x80x9d Circulation Research, 1994;75:41-54).
Collagenase and stromelysin activities have been demonstrated in fibroblasts isolated from inflamed gingiva (Uitto V. J., Applegren R., and Robinson P. J., xe2x80x9cCollagenase and neutral metalloproteinase activity in extracts from inflamed human gingiva,xe2x80x9d J. Periodontal Res., 1981;16:417-424), and enzyme levels have been correlated to the severity of gum disease (Overall C. M., Wiebkin O. W., and Thonard J. C., xe2x80x9cDemonstrations of tissue collagenase activity in vivo and its relationship to inflammation severity in human gingiva,xe2x80x9d J. Periodontal Res., 1987;22:81-88). Proteolytic degradation of extracellular matrix has been observed in corneal ulceration following alkali burns (Brown S. I., Weller C. A., and Wasserman H. E., xe2x80x9cCollagenolytic activity of alkali burned corneas,xe2x80x9d Arch. Ophthalmol., 1969;81:370-373). Thiol-containing peptides inhibit the collagenase isolated from alkali-bumed rabbit corneas (Burns F. R., Stack M. S., Gray R. D., and Paterson C. A., Invest. Ophthalmol., 1989;30:1569-1575).
Stromelysin is produced by basal keratinocytes in a variety of chronic ulcers (Saarialho-Kere U. K., Ulpu K., Pentland A. P., Birkedal-Hansen H., Parks W. O., and Welgus H. G., xe2x80x9cDistinct Populations of Basal Keratinocytes Express Stromelysin-1 and Stromelysin-2 in Chronic Wounds,xe2x80x9d J. Clin. Invest., 1994;94:79-88).
Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of the proliferating epidermis. Stromelysin-1 may thus prevent the epidermis from healing.
Davies et al., (Cancer Res., 1993;53:2087-2091) reported that a peptide hydroxamate, BB-94, decreased the tumor burden and prolonged the survival of mice bearing human ovarian carcinoma xenografts. A peptide of the conserved MMP propeptide sequence was a weak inhibitor of gelatinase A and inhibited human tumor cell invasion through a layer of reconstituted basement membrane (Melchiori A., Albili A., Ray J. M., and Stetler-Stevenson W. G., Cancer Res., 1992;52:2353-2356). The natural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showed blockage of tumor cell invasion in in vitro models (DeClerck Y. A., Perez N., Shimada H., Boone T. C., Langley K. E., and Taylor S. M., Cancer Res., 1992;52:701-708). Studies of human cancers have shown that gelatinase A is activated on the invasive tumor cell surface (Strongin A. Y., Marner B. L., Grant G. A., and Goldberg G. I., J. BioL Chem., 1993;268:14033-14039) and is retained there through interaction with a receptor-like molecule (Monsky W. L., Kelly T., Lin C.-Y., Yeh Y., Stetler-Stevenson W. G., Mueller S. C., and Chen W.-T., Cancer Res., 1993;53:3159-3164).
Inhibitors of MMPs have shown activity in models of tumor angiogenesis (Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P., Scanziani E., Brown P. D., and Giavazzi R., Journal of the National Cancer Institute, 1995;87:293 and Benelli R., Adatia R., Ensoli B., Stetler-Stevenson W. G., Santi L., and Albini A, Oncology Research, 1994;6:251-257).
Several investigators have demonstrated consistent elevation of stromelysin and collagenase in synovial fluids from osteo- and rheumatoid arthritis patients as compared to controls (Walakovits L. A., Moore V. L., Bhardwaj N., Gallick G. S., and Lark M. W., xe2x80x9cDetection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and post-traumatic knee injury,xe2x80x9d Arthritis Rheum., 1992;35:35-42; Zafarullah M., Pelletier J. P., Cloutier J. M., and Marcel-Pelletier J., xe2x80x9cElevated metalloproteinases and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia,xe2x80x9d J. Rheumatol., 1993;20:693-697). TIKP-1 and TIMP-2 prevented the formation of collagen fragments, but not proteoglycan fragments in both the bovine nasal and pig articular cartilage models for arthritis, while a synthetic peptide hydroxamate could prevent the formation of both fragments (Andrews H. J., Plumpton T. A., Harper G. P., and Cawston T. E., Agents Actions, 1992;37: 147-154; Ellis A. J., Curry V. A., Powell E. K., and Cawston T. E., Biochem. Biophys. Res. Commun., 1994;201:94-101).
Gijbels et al., (J. Clin. Invest., 1994;94:2177-2182) recently described a peptide hydroxamate, GM6001, that suppressed the development or reversed the clinical expression of experimental autoimmune encephalomyelitis (EAE) in a dose dependent manner, suggesting the use of MMP inhibitors in the treatment of autoimmune inflammatory disorders such as multiple sclerosis.
A recent study by Madri has elucidated the role of gelatinase A in the extravasation of T-cells from the blood stream during inflammation (Ramanic A. M., and Madri J. A., xe2x80x9cThe Induction of 72-kDa Gelatinase in T Cells upon Adhesion to Endothelial Cells is VCAM-1 Dependent,xe2x80x9d J. Cell Biology, 1994;125:1165-1178). This transmigration past the endothelial cell layer is coordinated with the induction of gelatinase A and is mediated by binding to the vascular cell adhesion molecule-1 (VCAM-1). Once the barrier is compromised, edema and inflammation are produced in the CNS. Also, leukocytic migration across the blood-brain barrier is known to be associated with the inflammatory response in EAE. Inhibition of the metalloproteinase gelatinase A would block the degradation of extracellular matrix by activated T-cells that is necessary for CNS penetration.
These studies provide the basis for the expectation that an effective inhibitor of gelatinase A and/or stromelysin- I would have value in the treatment of diseases involving disruption of extracellular matrix resulting in inflammation due to lymphocytic infiltration, inappropriate migration of metastatic or activated cells, or loss of structural integrity necessary for organ function.
Neuroinflammatory mechanisms are implicated in a broad range of acute and chronic neurodegenerative disorders, including stroke, head trauma, multiple sclerosis, and Alzheimer""s disease, to name a few (McGeer E. G. and McGeer P. L., xe2x80x9cNeurodegeneration and the immune systemxe2x80x9d. In: Calne D. B., ed. Neurodegenerative Diseases, W. B. Saunders, 1994:277-300). Other disorders that may involve neuroinflammatory mechanisms include amyotrophic lateral sclerosis (Leigh P. N., xe2x80x9cPathogenic mechanisms in amyotrophic lateral sclerosis and other motor neuron disordersxe2x80x9d. In: Calne D. B., ed., Neurodegenerative Diseases, W. B. Saunders, 1994:473-88), cerebral amyloid angiopathy (Mandybur T. I. and Balko G., xe2x80x9cCerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment,xe2x80x9d Clin. Neuropharm., 1992;15:241-7), AIDS (Gendelman H. E. and Tardieu M., xe2x80x9cMacrophages/microglia and the pathophysiology of CNS injuries in AIDS,xe2x80x9d J. Leukocyte Biol., 1994;56:387-8), Parkinson""s disease, Huntington""s disease, prion diseases, and certain disorders involving the peripheral nervous system, such as myasthenia gravis and Duchenne""s muscular dystrophy. Neuroinflammation, which occurs in response to brain injury or autoimmune disorders, has been shown to cause destruction of healthy tissue (Martin R., MacFarland H. F., and McFarlin D. E., xe2x80x9cImmunological aspects of demyelinating diseases,xe2x80x9d Annul Rev. Immunol., 1992; l 0:153-87; Clark R. K., Lee E. V., Fish C. J., et al., xe2x80x9cDevelopment of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study,xe2x80x9d Brain Res. Bull., 1993;31:565-72; Giulian D. and Vaca K., xe2x80x9cInflammatory glia mediate delayed neuronal damage after ischemia in the central nervous system,xe2x80x9d Stroke, 1993;24(Suppl 12):184-90; Patterson P. H., xe2x80x9cCytokines in Alzheimer""s disease and multiple sclerosis,xe2x80x9d Cur. Opinion Neurobiol., 1995;5:642-6; McGeer P. L., Rogers J., and McGeer E. G., xe2x80x9cNeuroimmune mechanisms in Alzheimer disease pathogenesis,xe2x80x9d Alzheimer Dis. Assoc. Disorders, 1994;8:149-58; Martin R. and McFarland H. F., xe2x80x9cImmunological aspects of experimental allergic encephalomyelitis and multiple sclerosis,xe2x80x9d Crit. Rev. Clin. Lab. Sci, 1995;32:121-82; Rogers J., Webster S., Lue L. F., et al., xe2x80x9cinflammation and Alzheimer""s disease pathogenesisxe2x80x9d. In: Neurobiology of Aging, 1996;17:681-686; Rothwell N. J. and Relton J. K., xe2x80x9cInvolvement of cytokines in acute neurodegeneration in the CNS,xe2x80x9d Neurosci Biobehav. Rev., 1993;17:217-27). The pathological profiles and clinical courses of these disorders differ widely, but they all have in common the participation of immune/inflammatory elements in the disease process. In particular, many neurodegenerative disorders are characterized by large numbers of reactive microglia in postmortem brain samples, indicative of an active inflammatory process (McGeer E. G. and McGeer P. L., supra., 1994).
Increasing attention is being directed toward inflammatory mechanisms in Alzheimer""s disease. Several lines of evidence support the involvement of neuroinflammation in Alzheimer""s disease: 1) There is a significant increase in inflammatory markers in the Alzheimer brain, including acute phase reactants, cytokines, complement proteins, and MHC molecules (McGeer et al., supra., 1994; Rogers et al., supra.); 2) There is evidence that xcex2-amyloid induces neurodegenerative changes primarily through interactions with inflammatory molecules, and that inflammation alone is sufficient to induce neurodegeneration (Rogers et al., supra); and 3) Growing epidemiological data indicate that anti-inflammatory therapy can delay the onset and slow the progression of Alzheimer""s disease (McGeer P. L. and Rogers J., xe2x80x9cAnti-inflammatory agents as a therapeutic approach to Alzheimer""s disease,xe2x80x9d Neurology, 1992;42:447-9; Canadian Study of Health and Aging, xe2x80x9cRisk factors for Alzheimer""s disease in Canada,xe2x80x9d Neurology, 1994;44:2073-80; Lucca U., Tettamanti M., Forloni G., and Spagnoli A., xe2x80x9cNonsteroidal antiinflammatory drug use in Alzheimer""s disease,xe2x80x9d Biol. Psychiatry, 1994;36:854-66; Hampel H. and Mxc3xcller N., xe2x80x9cinflammatory and immunological mechanisms in Alzheimer""s disease,xe2x80x9d DNandP, 1995;8:599-608; Breitner J. C. S., Gau B. A., Welsh K. A., et al., xe2x80x9cInverse association of anti-inflammatory treatments and Alzheimer""s disease: Initial results of a co-twin control study,xe2x80x9d Neurology, 1994;44:227-32; Breitner J. C. S., Welsh K. A., Helms M. J., et al., xe2x80x9cDelayed onset of Alzheimer""s disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs,xe2x80x9d Neurobiol. Aging, 1995;16:523-30; Andersen K., Launer L. J., Ott A., Hoes A. W., Breteler M. M. B., and Hofman A., xe2x80x9cDo nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer""s disease? The Rotterdam Study,xe2x80x9d Neurology, 1995;45:1441-5; Rich J. B., Rasmusson D. X., Folstein M. F., et al., xe2x80x9cNonsteroidal anti-inflammatory drugs in Alzheimer""s disease,xe2x80x9d Neurology, 1995;45:51-5; Aisen P. S., xe2x80x9cAnti-inflammatory therapy for Alzheimer""s disease,xe2x80x9d Dementia, 1995;9:173-82; Rogers et al., supra). Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), most commonly for the treatment of rheumatoid arthritis, decreases the probability of developing Alzheimer""s disease, and there is reason to believe that other anti-inflammatory agents may also be effective, although direct evidence for the efficacy of such treatments is lacking (Hamper and Mxc3xcller, supra., 1995). Furthermore, virtually all of the currently available compounds, which include corticosteroids, NSAIDs, antimalarial drugs, and colchicine, have serious drawbacks that make them undesirable in the treatment of chronic disorders. Glucocorticoids, which are in wide clinical use as anti-inflammatory/immunosuppressive drugs, can be directly neurotoxic and also are toxic to systemic organs at moderate to high doses. NSAIDs have gastrointestinal and renal side effects that obviate long-term use in most people, and few of them cross the blood-brain barrier in significant amounts. The toxic properties of chloroquine compounds and colchicine also are well known. An anti-inflammatory drug that is well-tolerated by patients and that crosses the blood-brain barrier has significant advantages for the treatment of acute and chronic degenerative diseases of the central nervous system.
Normal kidney function is dependent on the maintenance of tissues constructed from differentiated and highly specialized renal cells which are in a dynamic balance with their surrounding extracellular matrix (ECM) components (Davies M. et al., xe2x80x9cProteinases and glomerular matrix turnover,xe2x80x9d Kidney Int., 1992;41:671-678). Effective glomerular filtration requires that a semi-permeable glomerular basement membrane (GBM) composed of collagens, fibronectin, enactin, laminin and proteoglycans is maintained. A structural equilibrium is achieved by balancing the continued deposition of ECM proteins with their degradation by specific metalloproteinases (MMP). The MMP belong to a supergene family of zinc endopeptidases (Woessner J. F., xe2x80x9cMatrix metalloproteinases and their inhibitors in connective tissue remodelling,xe2x80x9dFASEB J., 1991;5:2145-2154). These proteins are first secreted as proenzymes and are subsequently activated in the extracellular space. These proteinases are in turn subject to counter balancing regulation of their activity by naturally occurring inhibitors referred to as TIMPs (tissue inhibitors of metalloproteinases).
Deficiency or defects in any component of the filtration barrier may have catastrophic consequences for longer term renal function. For example, in hereditary nephritis of Alport""s type, associated with mutations in genes encoding ECM proteins, defects in collagen assembly lead to progressive renal failure associated with splitting of the GBM and eventual glomerular and interstitial fibrosis. By contrast in inflammatory renal diseases such as glomerulonephritis, cellular proliferation of components of the glomerulus often precede obvious ultrastructural alteration of the ECM matrix. Cytokines and growth factors implicated in proliferative glomerulonephritis such as interleukin-1, tumor necrosis factor, and transforming growth factor beta can upregulate metalloproteinase expression in renal mesangial cells (Martin J. et al., xe2x80x9cEnhancement of glomerular mesangial cell neutral proteinase secretion by macrophages: role of interleukin 1,xe2x80x9d J. Immunol., 1986;137:525-529; Marti H. P. et al., xe2x80x9cHomology cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesangial cells,xe2x80x9d Biochem. J., 1993;291 :441-446; Marti H. P. et al., xe2x80x9cTransforming growth factor-b stimulates glomerular mesangial cell synthesis of the 72 kDa type IV collagenase,xe2x80x9d Am. J. Pathol., 1994;144:82-94). These metalloproteinases are believed to be intimately involved in the aberrant tissue remodeling and cell proliferation characteristic of renal diseases, such as, IgA nephropathy which can progress to through a process of gradual glomerular fibrosis and loss of functional GBM to end-stage renal disease. Metalloproteinase expression has already been well-characterized in experimental immune complex-mediated glomerulonephritis such as the anti-Thy 1.1 rat model (Bagchus W. M., Hoedemaeker P. J., Rozing J., Bakker W. W., xe2x80x9cGlomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies: A sequential histological and ultrastructural study in the rat,xe2x80x9d Lab. Invest., 1986;55:680-687; Lovett D. H., Johnson R. J., Marti H. P., Martin J., Davies M., Couser W. G., xe2x80x9cStructural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex mediated glomerulonephritis,xe2x80x9d Am. J. Pathol., 1992;141:85-98).
Unfortunately, at present, there are very limited therapeutic strategies for modifying the course of progressive renal disease. Although many renal diseases have an inflammatory component, their responses to standard immunosuppressive regimes are unpredictable and potentially hazardous to individual patients. The secondary consequences of gradual nephron failure such as activation of the reninangiotensin system, accompanied by individual nephron glomerular hyperfiltration and renal hypertension, may be effectively treated with ACE inhibitors or angiotensin II receptor antagonists; but at best, these compounds can only reduce the rate of GFR decline.
A novel strategy to treat at least some renal diseases has been suggested by recent observations of MMP behavior. A rat mesangial cell MMP has been cloned (MMP-2) which is regulated in a tissue specific manner, and in contrast to other cellular sources such as tumor cell lines, is induced by cytokines (Brown P. D., Levy A. T., Margulies I., Liotta L. A., Stetler-Stevenson W. G., xe2x80x9cIndependent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines,xe2x80x9d Cancer Res., 1990;50:6184-6191; Marti H. P. et al., xe2x80x9cHomology cloning of rat 72 kDa type IV collagenase: Cytokine and second-messenger inducibility in mesangial cells,xe2x80x9d Biochem. J., 1993;291 :441-446). While MMP-2 can specifically degrade surrounding ECM, it also affects the phenotype of adjacent mesangial cells. Inhibition of MMP-2 by antisense oligonucleotides or transfection techniques can induce a reversion of the proliferative phenotype of cultured mesangial cells to a quiescent or non-proliferative phenotype mimicking the natural in vitro behavior of these cells (Kitamura M. et al., xe2x80x9cGene transfer of metalloproteinase transin induces aberrant behaviour of cultured mesangial cells,xe2x80x9d Kidney Int., 1994;45:1580-1586; Turck J. et al., xe2x80x9cMatrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell proliferation and differentiation,xe2x80x9d J. Biol. Chem., 1996;271:15074-15083).
Inhibitors of MMP (MMPi) clearly have potential clinical applications in a host of diseases characterized by disturbance of extracellular matrix-cell interactions resulting in abnormal tissue remodeling (Vincenti M. P. et al., xe2x80x9cUsing inhibitors of metalloproteinases to treat arthritis,xe2x80x9d Arthritis Rheum., 1994;8:1115-1126; Grams F. et al., xe2x80x9cX-ray structures of human neutrophil collagenase complexed with peptide hydroxamate and peptide thiol inhibitors. Implications for substrate binding and rational drug design,xe2x80x9d Eur. J. Biochem., 1995;228:830-841).
We have identified a series of tricyclic heteroaromatic compounds and their derivatives that are inhibitors of matrix metalloproteinases, particularly collagenase-3, stromelysin-1 and gelatinase A, and thus useful as agents for the treatment of multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, left ventricular dilation, periodontal disease, corneal ulceration, treatment of bumns, decubital ulcers, wound repair, cancer, inflammation, pain, arthritis, osteoporosis, renal disease, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer""s disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson""s disease, Huntington""s diseases, prion diseases, myasthenic gravis, and Duchenne""s muscular dystrophy.
Accordingly, a first aspect of the present invention is a compound of Formula I 
wherein
n is zero or an integer of 1 or 2;
X is xe2x80x94Oxe2x80x94,
xe2x80x94S(O)pxe2x80x94 wherein p is zero or an integer of 1 or 2, 
xe2x80x83wherein R6 is hydrogen, alkyl, acyl, or benzyl,
xe2x80x94CH2xe2x80x94, or 
Z is 
CF2,
CHF,
xe2x80x94CH2xe2x80x94, 
xe2x80x83wherein R7 is OR8 wherein R8 is
hydrogen,
alkyl,
xe2x80x94(CH2)m-aryl wherein m is zero or an integer of 1 to 6,
xe2x80x94(CH2)m-heteroaryl wherein m is as defined above,
xe2x80x94(CH2)m-cycloalkyl wherein m is as defined above or 
xe2x80x83wherein R9 and R9a are either the same or different and are
hydrogen,
alkyl,
aryl,
arylalkyl,
heteroaryl, or
cycloalkyl;
R1, R2, R3, and R4 are either the same or different and are
hydrogen,
fluorine,
alkyl,
alkenyl,
alkynyl,
arylalkenyl,
heteroarylalkenyl,
arylapynyl,
heteroarylalkenyl,
xe2x80x94(CH2)m-aryl wherein m is as defined above,
xe2x80x94(CH2)m-heteroaryl wherein m is as defined above,
xe2x80x94(CH2)m-cycloalkyl wherein m is as defined above,
xe2x80x94(CH2)qxe2x80x94Xaxe2x80x94(CH2)q1-alkyl wherein Xa is O, S, SO, SO2, or NH, and q and q1 are each zero or an integer of 1 to 6, and the sum of q+q1 is not greater than six,
xe2x80x94(CH2)qxe2x80x94Xaxe2x80x94(CH2)q1-aryl wherein Xa, q, and q1 are as defined above,
xe2x80x94(CH2)qxe2x80x94Xaxe2x80x94(CH2)q1-heteroa wherein Xa, q, and q1 are as defined above, or
xe2x80x94(CH2)mxe2x80x94R10 wherein R10 is 
xe2x80x83wherein R11 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, or cycloalkyl, 
xe2x80x83wherein R11 is as defined above, 
xe2x80x83wherein R11 is as defined above, 
xe2x80x83wherein Y is nitrogen, oxygen, sulfur, or CH2 and R11 and n are as defined above and m is as defined above,
OR11 wherein R11 is as defined above, 
xe2x80x83wherein R11and R11a are the same or different and are as defined above for R11,
xe2x80x83xe2x80x94SR11 wherein R11 is as defined above, 
xe2x80x83wherein R11 is as defined above, 
xe2x80x83wherein R11 is as defined above 
xe2x80x83wherein R11 is as defined above, 
xe2x80x83wherein R11 and R11a are the same or different and are as defined above for R11, 
xe2x80x83wherein R11 is as defined above, 
xe2x80x83wherein R11 is as defined above, 
xe2x80x83wherein R11 is as defined above, or 
xe2x80x83wherein R11 and R11a are the same or different and are as defined above for R6, or 
xe2x80x83wherein R11 and R11a are as defined above; and
R5 is
xe2x80x94OR12 wherein R12 is
hydrogen,
alkyl, or
benzyl,
xe2x80x94NHxe2x80x94OR12 wherein R12 is as defined above, or
xe2x80x94SH;
with the proviso that when n is 1, X is xe2x80x94Oxe2x80x94, Z is 
and R5 is OR12 wherein R12 is as defined above, then at least one of R1, R2, R3, and R4 is not hydrogen; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
As matrix metalloproteinase inhibitors, the compounds of Formula I are useful as agents for the treatment of multiple sclerosis. They are also useful as agents for the treatment of atherosclerotic plaque rupture, aortic aneurism, heart failure, left ventricular dilation, restenosis, periodontal disease, corneal ulceration, treatment of bums, decubital ulcers, wound repair, cancer metastasis, tumor angiogenesis, inflammation, pain, arthritis, osteoporosis, renal disease, and other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer""s disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson""s disease, Huntington""s disease, prion diseases, myasthenia gravis, and Duchenne""s muscular dystrophy.
A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of compounds of Formula I.
In the compounds of Formula I, the term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 6 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The term xe2x80x9calkenylxe2x80x9d means a straight or branched unsaturated hydrocarbon radical having from 2 to 10 carbon atoms and includes, for example, ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, and the like.
The term xe2x80x9calkynylxe2x80x9d means a straight or branched triple bonded unsaturated hydrocarbon radical having from 2 to 10 carbon atoms and includes, for example, ethynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 3-heptynyl, 1-octynyl, 2-octynyl, 1-nonynyl, 2-nonynyl, 3-nonynyl, 4-nonynyl, 1-decynyl, 2-decynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d and xe2x80x9cthioalkoxyxe2x80x9d are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for xe2x80x9calkylxe2x80x9d.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring having 3 to 7 carbon atoms optionally containing an oxygen or sulfur atom and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term xe2x80x9carylxe2x80x9d means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined above for alkyl, nitro, cyano, carboxy, guanidino, amidino, SO3H, CHO, 
as defined above for alkyl, 
as defined above for alkyl, 
as defined above for alkyl, xe2x80x94(CH2)n2xe2x80x94NH2 wherein n2 is an integer of 1 to 5, xe2x80x94(CH2)n2xe2x80x94NHxe2x80x94alkyl as defined above for alkyl and n2, xe2x80x94(CH2)n2xe2x80x94N(alkyl)2 as defined above for alkyl and n2, 
as defined above for alkyl, and n2 and 
as defined above for alkyl and n2.
The term xe2x80x9carylalkylxe2x80x9d means an aromatic radical attached to an alkyl radical wherein aryl and alkyl are as defined above for example benzyl, phenylethyl, 3-phenylpropyl, (4-chlorophenyl)methyl, and the like.
The term xe2x80x9carylalkenylxe2x80x9d means an aromatic radical attached to an alkenyl radical wherein aryl and alkyl are as defined above.
The term xe2x80x9carylalkynylxe2x80x9d means an aromatic radical attached to an alkynyl radical wherein aryl and alkynyl are as defined above.
The term xe2x80x9cheteroarylxe2x80x9d means a 5- and 6-membered heteroaromatic radical containing 1 to 3 heteroatoms selected from N, O, and S and includes, for example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimidazol-5-yl, 2-, 4-, or 5-thiazolyl 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, or 2- or 5-thiadiazolyl optionally substituted by a substituent selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined above for alkyl, nitro, cyano, carboxy, guanidino, amidino, SO3H, CHO, 
as defined above for alkyl, 
as defined above for alkyl, 
as defined above for alkyl, xe2x80x94(CH2)n2xe2x80x94NH2 wherein n2 is an integer of 1 to 5, xe2x80x94(CH2)n2xe2x80x94NH-alkyl as defined above for alkyl and n2, xe2x80x94(CH2)n2xe2x80x94N(alkyl)2 as defined above for alkyl and n2, 
as defined above for alkyl, and n2 and 
as defined above for alkyl and n2.
The term xe2x80x9cheteroarylalkenylxe2x80x9d means a heteroaryl radical attached to an alkenyl radical wherein heteroaryl and alkenyl are as defined above.
The term xe2x80x9cheteroarylalkylxe2x80x9d means a heteroaryl radical attached to an alkynyl radical wherein heteroaryl and alkynyl are as defined above.
The term xe2x80x9cacylxe2x80x9d means a group of the formula 
wherein alkyl is as defined above.
xe2x80x9cHalogenxe2x80x9d is fluorine, chlorine, bromine, or iodine.
xe2x80x9cAlkali metalxe2x80x9d is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium, and the like.
Some of the compounds of Formula I are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharma. Sci., 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base forn may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharma Sci., 1977;66:1).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
A preferred compound of Formula I is 
wherein X, Z, R1, R2, R3, R4, and R5 are as defined above.
Another preferred compound of Formula I is 
wherein Z, R1, R2, R3, R4, and R5 are as defined above.
Another preferred compound of Formula I is 
wherein Z, R1, R2, R3, R4, and R5 are as defined above.
Another preferred compound of Formula I is 
wherein R1, R2, R3, R4, and R5 are as defined above.
A more preferred compound of Formula I is 
wherein R1, R2, R3, and R4 are as defined above.
A most preferred compound of Formula I is 
Particularly valuable in this embodiment of the invention is a compound selected from the group consisting of:
4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
N-Hydroxy-4-hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyramide;
N-Hydroxy-4-oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyramide;
4-(2,3-Dihydro-1-H-8-oxa-cyclopenta[a]inden-6-yl)-4-hydroxyiminobutyric acid;
4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-oxo-butyric acid;
4-Oxo-2-phenethyl-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-phenyl-pentanoic acid;
2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-6-phenyl-hexanoic acid;
2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-7-phenyl-heptanoic acid;
2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-8-phenyl-octanoic acid;
(S) 4-Hydroxyimino-2-phenethyl4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-8-phenyl-octanoic acid;
(S) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(S) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(S) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-pentanoic acid;
(S) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(S) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(S) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-pentanoic acid;
(S) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(S) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(S) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(S) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-oxo-2-phenethyl-butyric acid; (S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-8-phenyl-octanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-8-phenyl-octanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-5-phenyl-pentanoic acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)4-hydroxyimino-2-phenethyl-butyric acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-hexanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-7-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-heptanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-8-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-octanoic acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-hydroxyimino-butyric acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-6-(1,3-dioxo 1,3-dihydro-isoindol-2-yl)-hexanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-7-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-heptanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-8-(1,3dioxo-1,3-dihydro-isoindol-2-yl)-octanoic acid;
(S) 4(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)4-oxo-butyric acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-(1H-indol-3-ylmethyl)-4-oxo-butyric acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-4-oxo-butyric acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6yl)-2-[2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]--4--hydroxyimino-butyric acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-4-hydroxyimino-butyric acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-4--hydroxyimino-butyric acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(1H-indol-3-yl)-ethyl]-4-oxo-butyric acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-(1H-indol-3yl)pentanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-6-(1H-indol-3-yl)-hexanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-5-(1H-indol-3-yl)-pentanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-6-(1H-indol-3-yl)-hexanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-7-(1H-indol-3-yl)heptanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-8-(1H-indol-3-yl)-octanoic acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-hydroxyimino-2-(1H-indol-3-ylmethyl)-butyric acid;
(S) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-hydroxyimino-2-[2-(1H-indol-3-yl)-ethyl]-butyric acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-8-(1H-indol-3-yl)-octanoic acid;
(S) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-7-(1H-indol-3-yl)-heptanoic acid;
4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6yl)-4-hydroxy-butyric acid;
4-Hydroxy-2-phenethyl-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
2-[2-Hydroxy-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-phenyl-pentanoic acid;
2-[2-Hydroxy-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-6-phenyl-hexanoic acid;
2-[2-Hydroxy-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-7-phenyl-heptanoic acid;
2-[2-Hydroxy-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-8-phenyl-octanoic acid;
4-Hydroxy-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
4-Hydroxy4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
2-[2-Hydroxy-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
4(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-hydroxy-butyric acid;
4-Oxo-4--(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 4-Oxo-2-phenethyl-4--(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-8-phenyl-octanoic acid;
4-Hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 4-Hydroxyimino-2-phenethyl]-4--(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-8-phenyl-octanoic acid;
(S) 4-Oxo-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(S) 4-Oxo-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-oxo-imidazolidin-1-yl)-pentanoic acid;
(S) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(S) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(S) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-pentanoic acid;
(S) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(S) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-pentanoic acid;
4-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-4-oxo-butyric acid;
4-Hydroxyimino-4--(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-butyric acid;
4-Oxo-4--(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-butyric acid;
4-Hydroxyimino-4-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-butyric acid;
(S) 4-Oxo-2-phenethyl-4-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-butyric acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-8-phenyl-octanoic acid;
(S) 4-Hydroxyimino-2-phenethyl-4-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-butyric acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-8-phenyl-octanoic acid;
4-Oxo--4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-butyric acid;
4-Hydroxyimino--4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-butyric acid;
(S) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1 -ylmethyl)-butyric acid;
(S) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(S) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(S) 4-Hydroxyimino-4-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-phenethyl-butyric acid;
(S) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-8-phenyl-octanoic acid;
(S) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(S) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(S) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(S) 4(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-4-oxo-2-phenethyl-butyric acid;
(S) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-5-phenyl-pentanoic acid;
(S) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-6-phenyl-hexanoic acid;
(S) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-7-phenyl-heptanoic acid;
(S) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-8-phenyl-octanoic acid;
(R) 4-Hydroxyimino-2-phenethyl-4--(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-8-phenyl-octanoic acid;
(R) 2[-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(R) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(R) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-pentanoic acid;
(R) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(R) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-butyric acid;
(R) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-pentanoic acid;
(R) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(R) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(R) 4-Hydroxyimino-4-(6,7,8,9tetrahydro-dibenzofuran-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(R) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzofuran-3-yl)-ethyl]-5-(3,4,4trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-oxo-2-phenethyl-butyric acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-8-phenyl-octanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-8-phenyl-octanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl-2-hydroxyimino-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-5-phenyl-pentanoic acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-hydroxyimino-2-phenethyl-butyric acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-oxo-butyric acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-hexanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-7-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-heptanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-8-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-octanoic acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl-1ethyl]-4-hydroxyimino-butyric acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-Hydroxyimino-ethyl]-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-hexanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-7-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-heptanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-8-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-octanoic acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-4-oxo-butyric acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-(1H-indol-3-ylmethyl)-4-oxo-butyric acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-4-oxo-butyric acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(R) 4(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(4,4dimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-4-hydroxyimino-butyric acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-4-hydroxyimino-butyric acid;
R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-4-hydroxyimino-butyric acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-[2-(1H-indol-3-yl)-ethyl]-4-oxo-butyric acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-5-(1H-indol-3-yl)-pentanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-6-(1H-indol-3-yl)-hexanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-5-(1H-indol-3-yl)-pentanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-6-(1H-indol-3-yl)-hexanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-7-(1H-indol-3-yl)-heptanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-oxo-ethyl]-8-(1H-indol-3-yl)-octanoic acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-hydroxyimino-2-(1H-indol-3-ylmethyl)-butyric acid;
(R) 4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-4-hydroxyimino-2-[2-(1H-indol-3-yl)-ethyl]-butyric acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-8-(1H-indol-3-yl)-octanoic acid;
(R) 2-[2-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]inden-6-yl)-2-hydroxyimino-ethyl]-7-(1H-indol-3-yl)-heptanoic acid;
(R) 4-Oxo-2-phenethyl]-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-8-phenyl-octanoic acid;
(R) 4-Hydroxyimino-2-phenethyl-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-8-phenyl-octanoic acid;
(R) 4-Oxo-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(R) 4-Oxo-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(R) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(R) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(R) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-oxo-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(R) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]4-oxo-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(R) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-oxo-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-pentanoic acid;
(R) 2-(1 ,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxyimino-4- (6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(R) 2-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-4-hydroxyimino-4-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-butyric acid;
(R) 5-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-fluoren-2-yl)-ethyl]-pentanoic acid;
(R) 4-Oxo-2-phenethyl(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-butyric acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-8-phenyl-octanoic acid;
(R) 4-Hydroxyimino-2-phenethyl-4-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-butyric acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulen-2-yl)-ethyl]-8-phenyl-octanoic acid;
(R) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(R) 4-Oxo-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)ethyl]-butyric acid;
(R) 2-[2-Oxo-2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)-pentanoic acid;
(R) 4-Hydroxyimino-4-(9-methyl-6,7,8,9-tetrahydro-5H -carbazol-2-yl)-2-phenethyl-butyric acid;
(R) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-7-phenyl-heptanoic acid;
(R) 2-[2-Hydroxyimino-2-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-ethyl]-8-phenyl-octanoic acid;
(R) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-ylmethyl)-butyric acid;
(R) 4-Hydroxyimino-4-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-2-[2-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-ethyl]-butyric acid;
(R) 2-[2-Hydroxyimino-2-(6,7,8,9-tetrahydro-dibenzothiophen-3-yl)-ethyl]-5-(3,4,4-trimethyl-2,5-dioxo-imidazolidin-1-yl)-pentanoic acid;
(R) 4-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-4-oxo-2-phenethyl-butyric acid;
(R) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-5-phenyl-pentanoic acid;
(R) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-6-phenyl-hexanoic acid;
(R) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-7-phenyl-heptanoic acid; and
(R) 2-[2-(9-Methyl-6,7,8,9-tetrahydro-5H-carbazol-2-yl)-2-oxo-ethyl]-8-phenyl-octanoic acid; and corresponding isomers thereof; or a pharmaceutically acceptable salt thereof.
The compounds of Formula I are valuable inhibitors of a number of different matrix metalloproteinases. It has been shown previously that inhibitors of matrix metalloproteinases have efficacy in models of disease states like arthritis and metastasis that depend on modification of the extracellular matrix.
In vitro experiments were carried out which demonstrate the efficacy of compounds of Formula I as potent and specific inhibitors of a variety of matrix metalloproteinases. Experiments were carried out with the full-length and catalytic domains of the proteinases. Table 1 shows the activity of Examples 1-2 versus MMP-1FL (collagenase-1 full length enzyme), MMP-2CD (gelatinase A catalytic domain), MMP-2FL (gelatinase A full length enzyme), MMP-3CD (stromelysin-1 catalytic domain), MMP-7FL (matrilysin full length enzyme), MMP-9-FL (gelatinase B full length enzyme), MMP-13CD (collagenase-3 catalytic domain), and MMP-14CD (membrane-type MMP-1). IC50 values were determined using a thiopeptolide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (Ye Q.-Z., Johnson L. L., Hupe D. J., and Baragi V., xe2x80x9cPurification and Characterization of the Human Stromelysin Catalytic Domain Expressed in Escherichia coli,xe2x80x9d Biochemistry, 1992;31:11231-11235; Ye Q.-Z., Johnson L. L., Yu A. E., and Hupe D., xe2x80x9cReconstructed 19 kDa catalytic domain of gelatinase A is an active proteinase,xe2x80x9d Biochemistry, 1995;34:4702-4708.) MMP-13CD was expressed from a synthetic gene and purified from Escherichia coli cell culture according to a previously described method (Ye Q.-Z., Johnson L. L., and Baragi V., xe2x80x9cGene synthesis and expression in E. coli for PUMP, a human matrix metalloproteinase,xe2x80x9d Biochemical and Biophysical Research Communications, 1992; 186:143-149).
The following list contains abbreviations and acronyms used within the schemes and text:
Tricyclic aryl and tricyclic heteroaryl starting materials of formula (3) 
wherein
n is zero or an integer of 1 or 2; and
X is xe2x80x94Oxe2x80x94,
xe2x80x94S(O)pxe2x80x94 wherein p is zero or an integer of 1 or 2, 
xe2x80x83wherein R6 is hydrogen, alkyl, acyl, or benzyl,
xe2x80x94CH2xe2x80x94, or 
are either obtained from commercial sources (Xxe2x95x90Nxe2x88x92R6 wherein R6 is as defined above) or prepared using methods known in the art, e.g., Bachelet J. P. and Caubere P., J. Org. Chem., 1982;47:234-238; Ebel F., Helv. Chim. Acta, 1929;12:3-16; Vanrysselberghe V. et al., Ind. Eng. Chem. Res., 1996;35:3311-3318; Derouane D. et al., J. Chem. Soc., Chem. Commun., 1995;10:993-994; Miki Y. and Sugimoto Y., Seikiyu Gakkaishi, 1994;37:386-394; Miki Y. et al., Seikiyu Gakkaishi, 1992;35:332-338; Rankel L. A., Fuel Sci. Technol. Int., 1991;9:1435-1447; Siskin M. et al., Energy Fuels, 1990;4:482-488; Sundaram K. M. et al., Chem. Eng. Commun., 1988;71:53-71; Francisco M. A. et al., J. Org. Chem., 1988;53:596-600; Nagai M. et al., J. Catal., 1986;97:52-58; Miyake M. et al., Bull Chem. Soc. Japan, 1979;52:559-563; Ando W. et al., J. Chem. Soc. Chem. Commun, 1975;17:704-705; Fraser P. S. et al., J. Org. Chem., 1974;39:2509-2513; Cagniant P. et al., Bull. Soc. Chim. Fr., 1969;2:607-612; and Cagniant D. et al., Bull. Soc. Chim. Fr., 1969;2:601-606; U.S. Pat. Nos. 5,721,185, 5,670,680; International Published Patent Application WO 95/27717; Smith W. et al., J. Org. Chem., 1990;55:5301-5302; Mejer S., Pol. of Chem., 1979;53:2385-2388; Canonne P. et al., J. Org. Chem., 1980;45:1828-1835; Parham W. E., Synthesis, 1976;116-117; Japanese Patent Application JP 08191063 A2; Parhan W. E., J. Org. Chem., 1969;34:1899-1904; McClure K. F. et al., Bioorg. Med Chem. Lett., 1998;8:143-146.
The synthesis of starting materials for a compound of Formula I wherein X is xe2x80x94Oxe2x80x94 is shown in Scheme 1 (Ebel""s method). Thus, a compound of formula (1) wherein n is zero or an integer of 1 or 2 is reacted with phenol in the presence of sodium, or sodium hydride and the like in the presence of a solvent such as benzene, tetrahydrofuran and the like to afford a compound of formula (2). Cyclization of a compound of formula (2) in the presence of an acid such as, for example, polyphosphoric acid, para-toluenesulfonic acid and the like in the presence of a solvent such as benzene and the like affords a compound of formula (3). Ebel""s method for the synthesis of 1,2,4,4-tetrahydrodibenzofuran (3, n=1) was applied to the synthesis of 2,3-dihydro-1H-8-oxa-cyclopenta[a]indene (3, n=0).
The synthesis of compounds of Formula I where Z is CO, X is O, S(O)p, CH2, CO, NR6, R5 is OH, SH, and R1, R2, R3, and R4 and n are as defined above, can be made by the route shown in Scheme 2. The heterocycle (4) is acylated using Friedel-Crafts conditions with a compound of formula (6), prepared according to known methods such as, for example, as reported by Beckett et al., Synlett., 1993:137, or the corresponding anhydride of formula (5) in the presence of a Lewis acid such as, for example, FeCl3, AlCl3, ZnCl2, SnCl4, and the like either neat or in an inert solvent such as dichloromethane, 1,2-dichloroethane, nitrobenzene, and the like at about xe2x88x9240xc2x0 C. to about 120xc2x0 C. to give a compound of formulas (7 and 8). A compound of formula (7) can be deprotected using standard methodology known to one skilled in the art to give the corresponding carboxylic acid (8), which can then be condensed with R7NH2 to give a compound of formula (9). Alternatively, the carboxylic acid can be coupled with hydrogen sulfide after pretreatment with a suitable coupling agent such as, for example, 1,1xe2x80x2-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), and the like, and then condensed with R7NH2 to give a compound of formula (12). Compound (9) can be treated with a protected hydroxylamine derivative such as O-benzylhydroxylamine to give the protected hydroxamic acid derivative (10). This can be deprotected by hydrogenolysis using a catalyst, such as palladium/BaSO4 and hydrogen gas to give the hydroxamic acid (11).
The synthesis of compounds of Formula I where R2 and R4 are hydrogen, Z is CO, X is O, S(O)p, CH2, CO, NR6, R5 is OH, SH, and R1 and R3 and n are as defined above, can be made by the route shown in Scheme 3.
In Scheme 3, (R)- or (S)-4-benzyl-2-oxazolidinone can be reacted with an acid chloride (13), prepared using standard methodology known to one skilled in the art, in the presence of a non-nucleophilic base such as, for example, sodium hydride and the like in an inert solvent such as, for example, tetrahydroffiran and the like at temperatures between about xe2x88x9240xc2x0 C. and about reflux to give the N-acyl-oxazolidinone (14). The N-acyl-oxazolidinone (14) can be reacted with a suitable base such as, for example, potassium hexamethyldisilazide (KHDMS), lithium diisopropylamide (LDA), and the like followed by a bromoester (15), prepared in racemic form by brorination of the corresponding ester (16) with a suitable brominating reagent such as, for example, N-bromosuccinimide (NBS) and the like in a suitable solvent such as, for example, carbon tetrachloride and the like in the presence of ultraviolet light and a peroxide such as, for example, benzoyl peroxide and the like or in chiral form by reaction of an amino acid (17) with sodium nitrite and potassium bromide in aqueous hydrobromic acid followed by reacting the resulting bromoacid with a suitable coupling agent such as, for example, CDI, DCC, i-C4H9OCOCl, and the like and reacting the activated acid with a suitable alcohol such as, for example, methanol, ethanol, benzyl alcohol, and the like to give a compound of formula (18). A compound of formula (18), which may exist as a mixture of diastereoisomers, can be purified by a suitable technique such as, for example, chromatography on silica gel, and the like to give pure stereoisomers (PG=t-Bu or CH2Ph), which can be reacted with lithium hydroxide in THF-water followed by reaction of the resulting carboxylic acid with oxalyl chloride to give the corresponding acid chloride (19).
The acid chloride (19) is then reacted with a heterocycle of formula (4) using Friedel-Crafts conditions (as previously described) to give compound (20), which can be deprotected using methods known in the art to give compounds of formula (21).
The synthesis of compounds of Formula I where R1, R2, R3 (or R4) are hydrogen, Z is CO, X is O, S(O)p, CH2, CO, NR6, R5 is OH, and R4 (or R3) and n are as defined above, can be made by the route shown in Scheme 4. Friedel-Crafts acylation, in the presence of a Lewis acid such as, for example, FeCl3, AlCl3, ZnCl2, SnCl4, and the like either neat or in an inert solvent such as dichloromethane, 1,2-dichloroethane, nitrobenzene, and the like at about xe2x88x9240xc2x0 C. to about 120xc2x0 C., of the heterocycle (4) with bromoacetyl bromide gives compound (22). This is then condensed with the enolate of dimethyl malonate (generated by treating dimethyl malonate with a metal hydride, such as sodium hydride, in a solvent such as THF or dimethyl ether at temperatures ranging from xe2x88x9210xc2x0 C. to about 40xc2x0 C.) to yield compound (23). This can be alkylated by deprotonation with a metal hydride, such as sodium hydride, in a solvent such as DMF at temperatures ranging from xe2x88x9210xc2x0 C. to about 40xc2x0 C. followed by treatment with an alkylating agent (R3(4)X) to yield compound (24). Hydrolysis of the ester groups can be achieved by treatment with lithium hydroxide in a solvent such as dioxane at temperatures ranging from xe2x88x9210xc2x0 C. to about 40xc2x0 C. to give the corresponding diacid (25). Decarboxylation occurs by heating compound (25) in a solvent such as toluene with a base such as triethylamine, to give compound (26) which can then be condensed with R7NH2 to give a compound of formula (27).
Alternatively, as shown in Scheme 5, esters (28) can be alkylated by treatment with a base, such as lithium diisopropylamide in a solvent such as THF or dimethyl ether at temperatures ranging from xe2x88x9280xc2x0 C. to about 10xc2x0 C., and tert-butyl bromoacetate (29) to give the diester (30). This could be selectively deprotected using trifluoroacetic acid in the presence of a suitable carbonium ion scavenger such as, for example, anisole, thioanisole, triethylsilane, and the like in a solvent such as dichloromethane, chloroform, and the like, to give the ester acid (31). This can then be converted to the corresponding acid chloride (32) by treatment with a chlorinating agent such as oxalyl chloride or thionyl chloride in a solvent such as dichloromethane. Friedel-Crafts acylation, in the presence of a Lewis acid such as, for example, FeCl3, AlCl3, ZnCl2, SnCl4, and the like either neat or in an inert solvent such as dichloromethane, 1,2-dichloroethane, nitrobenzene, and the like at about xe2x88x9240xc2x0 C. to about 120xc2x0 C., of the heterocycle (4) with (32) gives compound (33). The ethyl ester is hydrolyzed by treatment with lithium hydroxide in a solvent such as dioxane at temperatures ranging from xe2x88x9210xc2x0 C. to about 40xc2x0 C. to give the corresponding acid (34) which can then be condensed with R7NH2 to give a compound of formula (35).
Alternatively, compounds of Formula I wherein Z is 
is OH or SH, and R1, R2, R3, R4, X and n are as defined in Formula I, can be synthesized according to the sequence outlined in Scheme 6.
In Scheme 6 the heterocycle (4), prepared according to the procedure outlined in Scheme 1, is allowed to react with a suitable acylating agent such as, for example, the acid chloride of formula (13) and the like in the presence of a Lewis acid such as, for example, FeCl3, AlCl3, ZnCl2, and the like either neat or in an inert solvent such as, for example, dichloromethane, nitrobenzene, and the like at about xe2x88x9240xc2x0 C. to about 120xc2x0 C. to give a compound of formula (36). A compound of formula (36) is allowed to react with a suitable strong base such as, for example, n-butyl lithium, lithium diisopropylamide, potassium hexamethyl-disilazide, and the like in an inert solvent such as, for example, tetrahydrofuran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (37), or N-fluorodibenzenesulfonamide (NFSI) for R2 equals fluorine, at temperatures at about xe2x88x9278xc2x0 C. to about 50xc2x0 C. to give a compound of formula (38). A compound of formula (38) is allowed to react with a suitable strong base such as, for example, n-butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide, and the like in an inert solvent such as, for example, tetrahydrofuran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (39) to give a compound of formula (40). A compound of formula (40) is deprotected using appropriate conditions such as, for example, trifluoroacetic acid or anhydrous hydrogen chloride in a suitable solvent such as, for example, dichloromethane or chloroform, with or without a carbonium ion scavenger such as, for example, triethylsilane, and the resulting carboxylic acid is resolved using methods known to one skilled in the art to give a compound of formula (41). A compound of formula (41) is condensed with R7NH2 to give a compound of formula (42). Alternatively, a compound of formula (41) is allowed to react with hydrogen sulfide after pretreatment with a suitable coupling agent such as, for example, 1,1xe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-dicyclohexylcarbodiimide, isobutyryl chloride, and the like, and then condensed with R7NH2 to give a compound of formula (43).
Alternatively, a compound of formula (40) is allowed to react with a suitable base such as, for example, n-butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide, and the like in an inert solvent such as, for example, tetrabydrofaran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (44) or NFSI for R3 equals fluorine, at temperatures at about xe2x88x9278xc2x0 C. to about 50xc2x0 C. to give a compound of formula (45). A compound of formula (45) is deprotected using appropriate conditions such as, for example, trifluoroacetic acid or anhydrous hydrogen chloride in a suitable solvent such as, for example, dichloromethane or chloroform, with or without a carbonium ion scavenger such as, for example, triethylsilane, and the resulting carboxylic acid is resolved using methods known to one skilled in the art to give a compound of formula (46). A compound of formula (46) is converted to compounds of formulas (47) and (48) according to the procedure described for the conversion of a compound of formula (41) to compounds of formulas (42) and (43), respectively. Alternatively, a compound of formula (45) is allowed to react with a suitable base such as, for example, n-butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide, and the like in an inert solvent such as, for example, tetrahydrofuran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (49) or NFSI for R4 equals fluorine, at temperatures at about xe2x88x9278xc2x0 C. to about 50xc2x0 C. to give a compound of formula (50). A compound of formula (50) is deprotected using appropriate conditions such as, for example, trifluoroacetic acid or anhydrous hydrogen chloride in a suitable solvent such as, for example, dichloromethane or chloroform, with or without a carbonium ion scavenger such as, for example, triethylsilane, and the resulting carboxylic acid is resolved using methods known to one skilled in the art to give a compound of formula (51). A compound of formula (51) is converted to compounds of formulas (52) and (53) according to the procedure described for the conversion of a compound of formula (41) to compounds of formulas (42) and (43), respectively.
Alternatively, compounds of Formula I wherein Z is 
is OH or SH, and, R1, R2, R3, R4, X, and n are as defined in Formula I are synthesized according to the sequence outlined in Scheme 7.
In Scheme 7, a compound of formula (54) is allowed to react with a suitable base such as, for example, n-butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide, and the like in an inert solvent such as, for example, tetrahydrofuran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (44) or NFSI for R3 equals fluorine, at temperatures at about xe2x88x9278xc2x0 C. to about 50xc2x0 C. to give a compound of formula (55). A compound of formula (55) is allowed to react with a suitable base such as, for example, n-butyl lithium lithium diisopropylamide, potassium hexamethyldisilazide, and the like in an inert solvent such as, for example, tetrahydrofliran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (56), prepared by allowing a compound of formula (4) to react with a suitable acylating agent such as BrCH2COCl in the presence of a suitable Lewis acid such as, for example, FeCl3, AlCl3, ZnCl2, and the like either neat or in an inert solvent such as, for example, dichloromethane, nitrobenzene, and the like at about xe2x88x9240xc2x0 C. to about 120xc2x0 C., to give a compound of formula (57). A compound of formula (57) is deprotected using appropriate conditions such as, for example, trifluoroacetic acid or anhydrous hydrogen chloride in a suitable solvent such as, for example, dichloromethane or chloroform, with or without a carbonium ion scavenger such as, for example, triethylsilane, and the resulting carboxylic acid can be resolved using methods known to one skilled in the art to give a compound of formula (58). A compound of formula (58) is converted to compounds of formulas (59) and (60) according to the procedure described in Scheme 6 for the conversion of a compound of formula (41) to compounds of formulas (42) and (43), respectively. Alternatively, a compound of formula (57) is allowed to react with a suitable base such as, for example, n-butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide, and the like in an inert solvent such as, for example, tetrahydrofuran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (61), or NFSI for R2 equals fluorine, at temperatures at about xe2x88x9278xc2x0 C. to about 50xc2x0 C. to give a compound of formula (62). A compound of formula (62) is deprotected using appropriate conditions such as, for example, trifluoroacetic acid or anhydrous hydrogen chloride in a suitable solvent such as, for example, dichloromethane or chloroform, with or without a carbomnum ion scavenger such as, for example, triethylsilane, and the resulting carboxylic acid can be resolved using methods known to one skilled in the art to give a compound of formula (63). A compound of formula (63) is converted to compounds of formulas (64) and (65) according to the procedure described in Scheme 6 for the conversion of a compound of formula (41) to compounds of formulas (42) and (43), respectively. Alternatively, a compound of formula (62) is allowed to react with a suitable base such as, for example, n-butyl lithium, lithium diisopropylamide, potassium hexamethyldisilazide, and the like in an inert solvent such as, for example, tetrahydrofuran, dimethyl ether, and the like at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. followed by a suitable alkylating agent of formula (66), or NFSI for R1 equals fluorine, at temperatures at about xe2x88x9278xc2x0 C. to about 50xc2x0 C. to give a compound of formula (50). A compound of formula (50) is converted via a compound of formula (51) to compounds of formulas (52) and (53) according to the procedure described in Scheme 6.
Compounds of Formula I wherein Z is CH(OH), Cxe2x95x90S, CF2, or CHF, and R5 is OH or SH, and R1, R2, R3, R4, X, and n are as defined in Formula I are synthesized according to the sequence outlined in Scheme 8.
In Scheme 8, keto-esters of formulas (7), (40), (45), (50), (57), or (62) can be hydrolyzed to the corresponding keto-acids, such as by stirring in aqueous hydrochloric acid at a concentration between about 2 M and about 6 M and at temperatures between about 25xc2x0 C. and reflux or by stirring in the presence of a suitable alkali metal hydroxide such as, for example, lithium, sodium, potassium hydroxide and the like in a suitable solvent such as, for example, methanol, ethanol, aqueous THF and the like at temperatures between about 0xc2x0 C. and reflux followed by acidification, and the keto-acids can be reduced using an appropriate hydride donating reagent such as sodium borohydride in ethanol, L- or S-selectride and the like in a suitable solvent such as, for example, toluene, tetrahydrofuran and the like to give the alcohol-acid (67). The alcohol-acid (67) can be silylated such as, for example, by allowing it to react with chlorotrimethylsilane (TMS-Cl) in the presence of a catalyst such as, for example, imidazole and the like in a suitable solvent such as, for example, anhydrous dimethylformamide (DMF) and the like to give the corresponding O-silyl alcohol-silyl ester, which can be fluorinated by allowing it to react with a suitable reagent such as, for example, dimethylaminosulfur trifluoride (DAST) and the like in a suitable solvent such as, for example, dichloromethane, chloroform and the like at temperatures between about xe2x88x9220xc2x0 C. and about reflux to give the corresponding fluoro-silyl ester, which can be hydrolyzed by stirring in aqueous hydrochloric acid at a concentration between about 2 M and about 6 M and at temperatures between about 25xc2x0 C. and reflux or by stirring in the presence of a suitable alkali metal hydroxide such as, for example, lithium, sodium, potassium hydroxide and the like in a suitable solvent such as, for example, methanol, ethanol, aqueous THF and the like at temperatures between about 0xc2x0 C. and reflux followed by acidification or by stirring in the presence of a suitable fluoride reagent such as, for example, tetra-n-butylammonium fluoride, aqueous hydrogen fluoride and the like in a suitable solvent such as, for example, tetrahydrofuran, acetonitrile and the like to give the fluoro-acid (68). The fluoro-acid (68) can be reacted with a suitable coupling agent such as, for example, CDI, DCC, i-C4H9OCOCl, and the like followed by hydrogen sulfide to give the fluoro-thioacid (69).
Alternatively, the keto-esters of formulas (7), (40), (45), (50), (57), or (62) can be allowed to react with a suitable fluorinating agent such as, for example, DAST and the like in a suitable solvent such as, for example, dichloromethane, chloroform and the like at temperatures between about xe2x88x9220xc2x0 C. and about reflux to give the corresponding fluoro-ester, which can be hydrolyzed such as by stirring in aqueous hydrochloric acid at a concentration between about 2 M and about 6 M and at temperatures between about 25xc2x0 C. and reflux or by stirring in the presence of a suitable alkali metal hydroxide such as, for example, lithium, sodium, potassium hydroxide and the like in a suitable solvent such as, for example, methanol, ethanol, aqueous THF and the like at temperatures between about 0xc2x0 C. and reflux followed by acidification to give the corresponding difluoro-acid (70). The difluoro-acid (70) can be allowed to react with a suitable coupling agent such as, for example, CDI, DCC, i-C4H9OCOCl, and the like followed by hydrogen sulfide to give the fluoro-thioacid (71).
Alternatively, keto-esters of formulas (7), (40), (45), (50), (57), or (62) can be hydrolyzed to the corresponding keto-acids, such as by stirring in aqueous hydrochloric acid at a concentration between about 2 M and about 6 M and at temperatures between about 25xc2x0 C. and reflux or by stirring in the presence of a suitable alkali metal hydroxide such as, for example, lithium, sodium, or potassium hydroxide and the like in a suitable solvent such as, for example, methanol, ethanol, or aqueous THF and the like at temperatures between about 0xc2x0 C. and reflux followed by acidification, and the keto-acids allowed to react with a suitable sulfur reagent such as, for example, Lawesson""s reagent and the like in a suitable solvent such as, for example, tetrahydrofuran and the like at temperatures between about 0xc2x0 C. and reflux to give the thioketo-acid (72). The thioketo-acid (72) can be allowed to react with a suitable coupling agent such as, for example, CDI, DCC, i-C4H9OCOCl, and the like followed by hydrogen sulfide to give the thioketo-thioacid (73). 
Compounds of formulas 5, 6, 8, 13, 15, 16, 17, 29, 37, 39, 44, or 49 are either commercially available or can be obtained by methods known in the art.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 5 or 10 to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gurns, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurism, heart failure, left ventricular dilation, restenosis, periodontal disease, corneal ulceration, treatment of burns, decubital ulcers, wound healing, cancer, inflammation, pain, arthritis, osteoporosis, renal disease, or other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes, or other activated migrating cells, acute and chronic neurodegenerative disorders including stroke, head trauma, spinal cord injury, Alzheimer""s disease, amyotrophic lateral sclerosis, cerebral amyloid angiopathy, AIDS, Parkinson""s disease, Huntington""s disease, prion diseases, myasthenia grayis, and Duchenne""s muscular dystrophy, the compounds utilized in the pharmaceutical methods of the invention are administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily. A daily dose range of about 25 mg to about 75 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optirumw effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.